Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 5, 2017
Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of ... more Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED...
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016
Despite the existence of several treatment options for smoking cessation, the rate of relapse aft... more Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation.
There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multip... more There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multiple indications (anxiety, seizures, alcohol withdrawal, muscular relaxation and anesthesia). Benzodiazepines are also addictive substances and a non-negligible fraction of regular users will develop dependence. There is currently no approved pharmacotherapy for benzodiazepine use disorder treatment and optimal strategies for treatment are unclear. In this review, we aimed to summarize the findings on off-label pharmacologic therapy that have been used for BZD dependence. One classical approach consists at providing a slow taper associated with counseling. Anti-epileptic drugs appear also to alleviate symptoms of withdrawal. The long-term strategies of maintenance therapy (with benzodiazepine) or of blocking therapy (with a GABA antagonist such as flumazenil) could provide some clinical benefit but have not yet been tested appropriately. Pregabalin appears promising and deserves further in...
Objectives: To evaluate and compare the effectiveness of available treatments for cocaine depende... more Objectives: To evaluate and compare the effectiveness of available treatments for cocaine dependence in schizophrenic patients.
Cocaine use affects approximately 13.4 million people, or 0.3% of the world's population between ... more Cocaine use affects approximately 13.4 million people, or 0.3% of the world's population between 15 and 64 years of age. Several authors have described drug addiction as a disease of the brain reward system. Given that the cholinergic system impacts reward mechanisms and drug self-administration, acetylcholine (ACh) might play an important role in the cocaine addiction process. We evaluated the efficacy of biperiden (a cholinergic antagonist) in reducing craving and the amount used, and in increasing compliance with treatment for cocaine/crack addiction. It was a study double-blind, randomised, placebo-controlled, 8-week trial of 111 cocaine or crack addicted male patients between 18 and 50 years old. Two groups were compared: placebo (n =55) or biperiden (n =56) combined with weekly sessions of brief group cognitive-behavioural therapy. The efficacy of treatment was evaluated according to the patients' compliance and several instruments: the Minnesota Cocaine Craving Scale, the Beck Depression and Anxiety Scales and a questionnaire assessing the amount of drug used. All of the patients attended weekly sessions for two months. We analysed the data considering the patients' intention to treat based on our last observation. Of the 56 patients in the biperiden group, 24 completed the treatment (42.8%) compared with only 11 patients in the placebo group (20%), which was a significant difference (p=0.009). Compliance with treatment was 118% higher in the biperiden group, which was also the group that presented a statistically significant reduction in the amount of cocaine/crack use (po0.001). There was statistically www.elsevier.com/locate/euroneurohttp://dx.Please cite this article as: Dieckmann, L.H.J., et al., Effects of biperiden on the treatment of cocaine/crack addiction: A randomised, double-blind, placebo-controlled trial. European Neuropsychopharmacology (2014), http://dx.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008
Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and v... more Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150mg/kg, i.p.), tamoxifen (1.0mg/kg, i.p.) and chelerythrine (1μg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0mg/g) and higher (6.0mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.
Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induc... more Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In order to counteract these limitations, this study characterized a precise neurotoxin-delivery strategy employing the bilateral intranigral administration protocol of rotenone as a reliable model of PD. We performed bilateral intranigral injections of rotenone (12 μg) and subsequent general activity (1, 10, 20, and 30 days after rotenone) and cognitive (7, 8, 15, and 30 days after rotenone) evaluations followed by neurochemical and immunohistochemical tests. We have observed that rotenone was able to produce a remarkable reduction on the percentage of tyrosine hydroxylase immunoreactive neurons (about 60%) within the substantia nigra pars compacta. Dopamine (DA) was severely depleted at 30 days after rotenone administration, similarly to its metabolites. In addition, an increase in DA turnover was detected at the same time-point. In parallel, striatal serotonin and its metabolite were found to be increased 30 days after the neurotoxic insult, without apparent modification in the serotonin turnover. Besides, motor behavior was impaired, mainly 1 day after rotenone. Furthermore, learning and memory processes were severely disrupted in different time-points, particularly at the training and test session (30 days). We now provide further evidence of a time-dependent neurodegeneration associated to cognitive impairment after the single bilateral intranigral administration of rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.
Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Effor... more Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.
Cannabis use disorder is the most commonly reported illegal substance use disorder in the general... more Cannabis use disorder is the most commonly reported illegal substance use disorder in the general population; although demand for assistance from health services is increasing internationally, only a minority of those with the disorder seek professional assistance. Treatment studies have been published, but pressure to establish public policy requires an updated systematic review of cannabis-specific treatments for adults. To evaluate the efficacy of psychosocial interventions for cannabis use disorder (compared with inactive control and/or alternative treatment) delivered to adults in an out-patient or community setting. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE, EMBASE, PsycINFO, the Cumulaive Index to Nursing and Allied Health Literature (CINAHL) and reference lists of articles. Searched literature included all articles published before July 2015. All randomised controlled studies examining a psychosocial intervention for cannabis use disorder (without pharmacological intervention) in comparison with a minimal or inactive treatment control or alternative combinations of psychosocial interventions. We used standard methodological procedures as expected by The Cochrane Collaboration. We included 23 randomised controlled trials involving 4045 participants. A total of 15 studies took place in the United States, two in Australia, two in Germany and one each in Switzerland, Canada, Brazil and Ireland. Investigators delivered treatments over approximately seven sessions (range, one to 14) for approximately 12 weeks (range, one to 56).Overall, risk of bias across studies was moderate, that is, no trial was at high risk of selection bias, attrition bias or reporting bias. Further, trials included a large total number of participants, and each trial ensured the fidelity of treatments provided. In contrast, because of the nature of the interventions provided, participant blinding was not possible, and reports of researcher blinding often were unclear or were not provided. Half of the reviewed studies included collateral verification or urinalysis to confirm self report data, leading to concern about performance and detection bias. Finally, concerns of other bias were based on relatively consistent lack of assessment of non-cannabis substance use or use of additional treatments before or during the trial period.A subset of studies provided sufficient detail for comparison of effects of any intervention versus inactive control on primary outcomes of interest at early follow-up (median, four months). Results showed moderate-quality evidence that approximately seven out of 10 intervention participants completed treatment as intended (effect size (ES) 0.71, 95% confidence interval (CI) 0.63 to 0.78, 11 studies, 1424 participants), and that those receiving psychosocial intervention used cannabis on fewer days compared with those given inactive control (mean difference (MD) 5.67, 95% CI 3.08 to 8.26, six studies, 1144 participants). In addition, low-quality evidence revealed that those receiving intervention were more likely to report point-prevalence abstinence (risk ratio (RR) 2.55, 95% CI 1.34 to 4.83, six studies, 1166 participants) and reported fewer symptoms of dependence (standardised mean difference (SMD) 4.15, 95% CI 1.67 to 6.63, four studies, 889 participants) and cannabis-related problems compared with those given inactive control (SMD 3.34, 95% CI 1.26 to 5.42, six studies, 2202 participants). Finally, very low-quality evidence indicated that those receiving intervention reported using fewer joints per day compared with those given inactive control (SMD 3.55, 95% CI 2.51 to 4.59, eight studies, 1600 participants). Notably, subgroup analyses found that interventions of more than four sessions delivered over longer than one month (high intensity) produced consistently improved outcomes (particularly in terms of cannabis use frequency and severity of dependence) in the short term as compared with low-intensity interventions.The most consistent evidence supports the use of cognitive-behavioural therapy (CBT), motivational enhancement therapy (MET) and particularly their combination for assisting with reduction of cannabis use frequency at early follow-up (MET: MD 4.45, 95% CI 1.90 to 7.00, four studies, 612 participants; CBT: MD 10.94, 95% CI 7.44 to 14.44, one study, 134 participants; MET + CBT: MD 7.38, 95% CI 3.18 to 11.57, three studies, 398 participants) and severity of dependence (MET: SMD 4.07, 95% CI 1.97 to 6.17, two studies, 316 participants; MET + CBT: SMD 7.89, 95% CI 0.93 to 14.85, three studies, 573 participants), although no particular intervention was consistently effective at nine-month follow-up or later. In addition, data from five out of six studies supported the utility of adding voucher-based incentives for cannabis-negative urines to enhance treatment effect on cannabis use frequency. A single study found contrasting results throughout…
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 5, 2017
Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of ... more Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED...
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016
Despite the existence of several treatment options for smoking cessation, the rate of relapse aft... more Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation.
There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multip... more There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multiple indications (anxiety, seizures, alcohol withdrawal, muscular relaxation and anesthesia). Benzodiazepines are also addictive substances and a non-negligible fraction of regular users will develop dependence. There is currently no approved pharmacotherapy for benzodiazepine use disorder treatment and optimal strategies for treatment are unclear. In this review, we aimed to summarize the findings on off-label pharmacologic therapy that have been used for BZD dependence. One classical approach consists at providing a slow taper associated with counseling. Anti-epileptic drugs appear also to alleviate symptoms of withdrawal. The long-term strategies of maintenance therapy (with benzodiazepine) or of blocking therapy (with a GABA antagonist such as flumazenil) could provide some clinical benefit but have not yet been tested appropriately. Pregabalin appears promising and deserves further in...
Objectives: To evaluate and compare the effectiveness of available treatments for cocaine depende... more Objectives: To evaluate and compare the effectiveness of available treatments for cocaine dependence in schizophrenic patients.
Cocaine use affects approximately 13.4 million people, or 0.3% of the world's population between ... more Cocaine use affects approximately 13.4 million people, or 0.3% of the world's population between 15 and 64 years of age. Several authors have described drug addiction as a disease of the brain reward system. Given that the cholinergic system impacts reward mechanisms and drug self-administration, acetylcholine (ACh) might play an important role in the cocaine addiction process. We evaluated the efficacy of biperiden (a cholinergic antagonist) in reducing craving and the amount used, and in increasing compliance with treatment for cocaine/crack addiction. It was a study double-blind, randomised, placebo-controlled, 8-week trial of 111 cocaine or crack addicted male patients between 18 and 50 years old. Two groups were compared: placebo (n =55) or biperiden (n =56) combined with weekly sessions of brief group cognitive-behavioural therapy. The efficacy of treatment was evaluated according to the patients' compliance and several instruments: the Minnesota Cocaine Craving Scale, the Beck Depression and Anxiety Scales and a questionnaire assessing the amount of drug used. All of the patients attended weekly sessions for two months. We analysed the data considering the patients' intention to treat based on our last observation. Of the 56 patients in the biperiden group, 24 completed the treatment (42.8%) compared with only 11 patients in the placebo group (20%), which was a significant difference (p=0.009). Compliance with treatment was 118% higher in the biperiden group, which was also the group that presented a statistically significant reduction in the amount of cocaine/crack use (po0.001). There was statistically www.elsevier.com/locate/euroneurohttp://dx.Please cite this article as: Dieckmann, L.H.J., et al., Effects of biperiden on the treatment of cocaine/crack addiction: A randomised, double-blind, placebo-controlled trial. European Neuropsychopharmacology (2014), http://dx.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008
Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and v... more Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150mg/kg, i.p.), tamoxifen (1.0mg/kg, i.p.) and chelerythrine (1μg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0mg/g) and higher (6.0mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.
Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induc... more Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In order to counteract these limitations, this study characterized a precise neurotoxin-delivery strategy employing the bilateral intranigral administration protocol of rotenone as a reliable model of PD. We performed bilateral intranigral injections of rotenone (12 μg) and subsequent general activity (1, 10, 20, and 30 days after rotenone) and cognitive (7, 8, 15, and 30 days after rotenone) evaluations followed by neurochemical and immunohistochemical tests. We have observed that rotenone was able to produce a remarkable reduction on the percentage of tyrosine hydroxylase immunoreactive neurons (about 60%) within the substantia nigra pars compacta. Dopamine (DA) was severely depleted at 30 days after rotenone administration, similarly to its metabolites. In addition, an increase in DA turnover was detected at the same time-point. In parallel, striatal serotonin and its metabolite were found to be increased 30 days after the neurotoxic insult, without apparent modification in the serotonin turnover. Besides, motor behavior was impaired, mainly 1 day after rotenone. Furthermore, learning and memory processes were severely disrupted in different time-points, particularly at the training and test session (30 days). We now provide further evidence of a time-dependent neurodegeneration associated to cognitive impairment after the single bilateral intranigral administration of rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.
Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Effor... more Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.
Cannabis use disorder is the most commonly reported illegal substance use disorder in the general... more Cannabis use disorder is the most commonly reported illegal substance use disorder in the general population; although demand for assistance from health services is increasing internationally, only a minority of those with the disorder seek professional assistance. Treatment studies have been published, but pressure to establish public policy requires an updated systematic review of cannabis-specific treatments for adults. To evaluate the efficacy of psychosocial interventions for cannabis use disorder (compared with inactive control and/or alternative treatment) delivered to adults in an out-patient or community setting. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE, EMBASE, PsycINFO, the Cumulaive Index to Nursing and Allied Health Literature (CINAHL) and reference lists of articles. Searched literature included all articles published before July 2015. All randomised controlled studies examining a psychosocial intervention for cannabis use disorder (without pharmacological intervention) in comparison with a minimal or inactive treatment control or alternative combinations of psychosocial interventions. We used standard methodological procedures as expected by The Cochrane Collaboration. We included 23 randomised controlled trials involving 4045 participants. A total of 15 studies took place in the United States, two in Australia, two in Germany and one each in Switzerland, Canada, Brazil and Ireland. Investigators delivered treatments over approximately seven sessions (range, one to 14) for approximately 12 weeks (range, one to 56).Overall, risk of bias across studies was moderate, that is, no trial was at high risk of selection bias, attrition bias or reporting bias. Further, trials included a large total number of participants, and each trial ensured the fidelity of treatments provided. In contrast, because of the nature of the interventions provided, participant blinding was not possible, and reports of researcher blinding often were unclear or were not provided. Half of the reviewed studies included collateral verification or urinalysis to confirm self report data, leading to concern about performance and detection bias. Finally, concerns of other bias were based on relatively consistent lack of assessment of non-cannabis substance use or use of additional treatments before or during the trial period.A subset of studies provided sufficient detail for comparison of effects of any intervention versus inactive control on primary outcomes of interest at early follow-up (median, four months). Results showed moderate-quality evidence that approximately seven out of 10 intervention participants completed treatment as intended (effect size (ES) 0.71, 95% confidence interval (CI) 0.63 to 0.78, 11 studies, 1424 participants), and that those receiving psychosocial intervention used cannabis on fewer days compared with those given inactive control (mean difference (MD) 5.67, 95% CI 3.08 to 8.26, six studies, 1144 participants). In addition, low-quality evidence revealed that those receiving intervention were more likely to report point-prevalence abstinence (risk ratio (RR) 2.55, 95% CI 1.34 to 4.83, six studies, 1166 participants) and reported fewer symptoms of dependence (standardised mean difference (SMD) 4.15, 95% CI 1.67 to 6.63, four studies, 889 participants) and cannabis-related problems compared with those given inactive control (SMD 3.34, 95% CI 1.26 to 5.42, six studies, 2202 participants). Finally, very low-quality evidence indicated that those receiving intervention reported using fewer joints per day compared with those given inactive control (SMD 3.55, 95% CI 2.51 to 4.59, eight studies, 1600 participants). Notably, subgroup analyses found that interventions of more than four sessions delivered over longer than one month (high intensity) produced consistently improved outcomes (particularly in terms of cannabis use frequency and severity of dependence) in the short term as compared with low-intensity interventions.The most consistent evidence supports the use of cognitive-behavioural therapy (CBT), motivational enhancement therapy (MET) and particularly their combination for assisting with reduction of cannabis use frequency at early follow-up (MET: MD 4.45, 95% CI 1.90 to 7.00, four studies, 612 participants; CBT: MD 10.94, 95% CI 7.44 to 14.44, one study, 134 participants; MET + CBT: MD 7.38, 95% CI 3.18 to 11.57, three studies, 398 participants) and severity of dependence (MET: SMD 4.07, 95% CI 1.97 to 6.17, two studies, 316 participants; MET + CBT: SMD 7.89, 95% CI 0.93 to 14.85, three studies, 573 participants), although no particular intervention was consistently effective at nine-month follow-up or later. In addition, data from five out of six studies supported the utility of adding voucher-based incentives for cannabis-negative urines to enhance treatment effect on cannabis use frequency. A single study found contrasting results throughout…
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